Postoperative adhesion formation is a major clinical problem because of their complications, such as bowel obstruction (Ellis H Eur J Surg Supp 15-9, 1997), chronic pelvic pain (Duffy D M, DiZerega G S, J Reprod Med 41:19-26, 1996) and female infertility (Gomel V: Fertil Steril 40:607-611, 1983) and prolonged surgical time and postoperative complications (when additional surgical procedures are needed). The most common cause is prior surgery. The most frequent surgical procedures implicated in significant adhesion formation are gynecologic, cardiovascular, and general abdominal surgery. This is true for traditional surgery, as well as laparoscopic surgery.
The pathophysiological events involved in adhesion formation are well known (Holmdahl L et al, Eur J Surg Suppl 56-62, 1997 and DiZerega G S, Eur J Surg Suppl 10-16, 1997) and can be summarized as follows: A peritoneal defect will cause exudation, fibrin deposition, followed by an inflammatory reaction, fibrinolysis and complete reepithelialisation within 3 to 8 days. This rapid healing is a consequence of the regeneration of the mesothelial layer from multiple foci in the lesion and not from the borders as is found during repair of another epithelium. The direct consequence of this is that the duration of reepithelialisation is independent of the denuded area in the peritoneum. If this rapid healing process fails by an overload of fibrin (e.g. through bleeding), by a decreased fibrinolysis (e.g. as a consequence of a more severe tissue trauma), resulting in a persistent fibrin matrix (Bittinger F, J Surg Res 82:28-33, 1999), or by the presence of a prolonged inflammatory reaction (e.g. by an infection or by suture material), this will lead to prolonged fibroblast proliferation, collagen deposition, angiogenesis and ultimately adhesion formation.
Exact data on the prevalence and severity of these consequences are not available since adhesions vary with the severity of surgery, and since systematic second look laparoscopies cannot be performed for obvious ethical reasons. Adhesions occur in over 50% of patients following a laparotomy, whereas the risk of reintervention because of adhesions following a laparotomy was recently estimated at 35% within 10 years in a large survey in Scotland (Ellis H. et al, Lancet 353:1476-1480, 1999). Adhesion formation is a major problem following surgical procedures and is a frequent cause of postoperative pain and of infertility. Adhesions are the major cause of intestinal obstruction and it is estimated that following an intra-abdominal procedure, adhesions occur in some 50 to 80 percent of patients.
Thus, there is a need in the art for methods and compositions for inhibiting adhesion formation in patients.
Endoscopy also called minimal access surgery has become widely used over the last years because of clear-cut advantages of a decreased postoperative morbidity, less pain and a shorter hospitalisation. These procedures require by means of an insufflation system or an irrigation system a distension to permit visualisation. Endoscopic surgery uses a gas stream such as carbon dioxide gas (CO2). Since anoxemia is a major cause and/or cofactor of adhesion formation, a gas mixture of CO2/O2 in suitable proportions has now been used to reduce adhesion formation has been proposed (U.S. Pat. No. 6,428,500).
However pneumoperitoneum, and in particular CO2 pneumoperitoneum, remains a co-factor in adhesion formation.
We now have evaluated in a laparoscopic mouse model the specific effect of cooling upon adhesion formation under CO2 pneumoperitoneum and CO2 /O2.
First, the effect of body temperature upon basal and pneumoperitoneum-enhanced adhesion formation was evaluated in mice placed at room temperature (RT) or at 37° C. Secondly, the effect of using humidified air for ventilation upon body temperature was evaluated. Subsequently, the effect of body temperature (range: 32° C. to 37° C.) upon adhesion formation was evaluated in detail. Finally, in mice with a body temperature kept at 37° C., the pneumoperitoneum-enhanced adhesion formation by pure CO2, together with the effects of adding 3% or 12% of oxygen, were confirmed.
It was surprisingly found that pneumoperitoneum-enhanced adhesion formation is much less at lower body temperatures.
A decrease in body temperature can be the consequence of anaesthesia and of desiccation when non-humidified gas is used either for ventilation or for pneumoperitoneum. We confirmed at an environmental temperature of 37° C. that the addition of 3% of oxygen to the pneumoperitoneum decreases adhesion formation and that 12% of oxygen causes more adhesions than 3%.
Moreover it was surprisingly found and clearly demonstrated that hypothermia reduces adhesion formation. A system for inducing and controlling hypothermia has been designed for prevention of adhesion prevention in mammalian, preferably human, surgery and preferably for endoscopic surgery.